Substitutions of fluorine atoms and phenoxy groups in the synthesis of quinoxaline 1,4-di-N-oxide derivatives.

The unexpected substitution of fluorine atoms and phenoxy groups attached to quinoxaline or benzofuroxan rings is described. The synthesis of 2-benzyl- and 2-phenoxy- 3-methylquinoxaline 1,4-di-N-oxide derivatives was based on the classical Beirut reaction. The tendency of fluorine atoms linked to quinoxaline or benzofuroxan rings to be replaced by a methoxy group when dissolved in an ammonia saturated solution of methanol was clearly demonstrated. In addition, 2-phenoxyquinoxaline 1,4-di-N-oxide derivatives became 2-aminoquinoxaline 1,4-di-N-oxide derivatives in the presence of gaseous ammonia

Quinoxaline 1,4-di-N-oxide and the Potential for Treating Tuberculosis

New drugs active against drug-resistant tuberculosis are urgently needed to extend the range of TB treatment options to cover drug resistant infections. Quinoxaline derivatives show very interesting biological properties (antibacterial, antiviral, anticancer, antifungal, antihelmintic, insecticidal) and evaluation of their medicinal chemistry is still in progress. In this review we report the properties and the recent developments of quinoxaline 1,4-di-N-oxide derivatives as potential anti-tuberculosis agents. Specific agents are reviewed that have excellent antitubercular drug properties, are active on drug resistant strains and non-replicating mycobacteria. The properties of select analogs that have in vivo activity in the low dose aerosol infection model in mice will be reviewed

Derivados de 1,4-di-N-óxido de quinoxalina y enfermedades olvidadas

Las enfermedades olvidadas son un grupo de enfermedades infecciosas médicamente diversas entre las que se encuentran tuberculosis, malaria, leishmaniasis y la enfermedad de Chagas, que afectan a millares de personas en todo el mundo pero, principalmente, a la gente pobre en países en vías de desarrollo. Son un reto para la Salud Pública Internacional ya que no existen vacunas parar controlarlas y los medicamentos existentes para su tratamiento no son adecuados. La necesidad de buscar nuevas terapias económicamente accesibles para la población afectada es cada vez más urgente y palpable, lo que ha dado lugar a la puesta en marcha de nuevas iniciativas internacionales que buscan la erradicación de estas enfermedades. A lo largo de los años, nuestro grupo de investigación ha llevado a cabo el diseño y la síntesis, mediante métodos sintéticos sencillos y de bajo coste, de diversos derivados de 1,4-di-N-óxido de quinoxalina con el objetivo de encontrar nuevos líderes para el tratamiento de algunas enfermedades olvidadas. Como resultado de varios proyectos de investigación, se han desarrollado nuevas estructuras activas como agentes antituberculosos, antimaláricos, antichagas y, más recientemente, como agentes antileishmania. Este resumen presenta los resultados más importantes obtenidos en este campo, de los que se puede concluir que el núcleo de 1,4-di-N-óxido de quinoxalina representa un posible avance en la búsqueda de nuevos compuestos activos

Assessing gastro-intestinal related quality of life in cystic fibrosis: Validation of PedsQL GI in children and their parents

Background: Most patients with cystic fibrosis (CF) suffer from pancreatic insufficiency, leading to fat malabsorption, malnutrition and abdominal discomfort. Until recently, no specific tool was available for assessing gastro-intestinal related quality of life (GI QOL) in patients with CF. As the Horizon2020 project MyCyFAPP aims to improve GI QOL by using a newly designed mobile application, a sensitive and reliable outcome measure was needed. We aimed to study the applicability of the existing child-specific Pediatric Quality of Life Inventory, Gastrointestinal Symptoms Scales and Module (PedsQL GI) in children with CF. Methods: A multicenter, prospective observational study was performed in 6 European centers to validate the PedsQL GI in children with CF during 3 months. Results: In total, 248 children and their parents were included. Within-patient variability of PedsQL GI was low (24.11), and there was reasonable agreement between children and parents (ICC 0.681). Nine of 14 subscales were informative (no ceiling effect). The PedsQL GI and the median scores for 4 subscales were significantly lower in patients compared to healthy controls. Positive associations were found between PedsQL GI and age (OR = 1.044, p = 0.004) and between PedsQL GI and BMI z-score (OR = 1.127, p = 0.036). PedsQL GI correlated with most CFQ-R subscales (r 0.268 to 0.623) and with a Visual Analogue Scale (r = 0.20). Conclusions: PedsQL GI is a valid and applicable instrument to assess GI QOL in children with CF. Future research efforts should examine the responsiveness of the CF PedsQL GI to change in the context of clinical interventions and trials

Derivados de 1,4-di-N-óxido de quinoxalina y enfermedades olvidadas

Las enfermedades olvidadas son un grupo de enfermedades infecciosas médicamente diversas entre las que se encuentran tuberculosis, malaria, leishmaniasis y la enfermedad de Chagas, que afectan a millares de personas en todo el mundo pero, principalmente, a la gente pobre en países en vías de desarrollo. Son un reto para la Salud Pública Internacional ya que no existen vacunas parar controlarlas y los medicamentos existentes para su tratamiento no son adecuados. La necesidad de buscar nuevas terapias económicamente accesibles para la población afectada es cada vez más urgente y palpable, lo que ha dado lugar a la puesta en marcha de nuevas iniciativas internacionales que buscan la erradicación de estas enfermedades. A lo largo de los años, nuestro grupo de investigación ha llevado a cabo el diseño y la síntesis, mediante métodos sintéticos sencillos y de bajo coste, de diversos derivados de 1,4-di-N-óxido de quinoxalina con el objetivo de encontrar nuevos líderes para el tratamiento de algunas enfermedades olvidadas. Como resultado de varios proyectos de investigación, se han desarrollado nuevas estructuras activas como agentes antituberculosos, antimaláricos, antichagas y, más recientemente, como agentes antileishmania. Este resumen presenta los resultados más importantes obtenidos en este campo, de los que se puede concluir que el núcleo de 1,4-di-N-óxido de quinoxalina representa un posible avance en la búsqueda de nuevos compuestos activos

Synthesis and antiplasmodial activity of 3-furyl and 3-thienylquinoxaline-2-carbonitrile 1,4-di-N-oxide derivatives

The aim of this study was to identify new compounds active against Plasmodium falciparum based on our previous research carried out on 3-phenylquinoxaline- 2-carbonitrile 1,4-di-N-oxide derivatives. Twelve compounds were synthesized and evaluated for antimalarial activity. Eight of them showed an IC50 < 1 μM against the 3D7 strain. Derivative 1 demonstrated high potency (IC50= 0.63 μM) and good selectivity (SI=10.35), thereby becoming a new lead-compound

CDH22 hypermethylation is an independent prognostic biomarker in breast cancer

Abstract Background Cadherin-like protein 22 (CDH22) is a transmembrane glycoprotein involved in cell-cell adhesion and metastasis. Its role in cancer is controversial because it has been described as being upregulated in colorectal cancer, whereas it is downregulated in metastatic melanoma. However, its status in breast cancer (BC) is unknown. The purpose of our study was to determine the molecular status and clinical value of CDH22 in BC. Results We observed by immunohistochemistry that the level of CDH22 expression was lower in BC tissues than in their matched adjacent-to-tumour and non-neoplastic tissues from reduction mammoplasties. Since epigenetic alteration is one of the main causes of gene silencing, we analysed the hypermethylation of 3 CpG sites in the CDH22 promoter by pyrosequencing in a series of 142 infiltrating duct BC cases. CDH22 was found to be hypermethylated in tumoral tissues relative to non-neoplastic mammary tissues. Importantly, this epigenetic alteration was already present in adjacent-to-tumour tissues, although to a lesser extent than in tumoral samples. Furthermore, CDH22 gene regulation was dynamically modulated in vitro by epigenetic drugs. Interestingly, CDH22 hypermethylation in all 3 CpG sites simultaneously, but not expression, was significantly associated with shorter progression-free survival ( p\u2009= \u20090.015) and overall survival ( p \u2009=\u20090.021) in our patient series. Importantly, CDH22 hypermethylation was an independent factor that predicts poor progression-free survival regardless of age and stage ( p \u2009=\u20090.006). Conclusions Our results are the first evidence that CDH22 is hypermethylated in BC and that this alteration is an independent prognostic factor in BC. Thus, CDH22 hypermethylation could be a potential biomarker of poor prognosis in BC

Quinoxaline 1,4-di-N-oxide and the Potential for Treating Tuberculosis

New drugs active against drug-resistant tuberculosis are urgently needed to extend the range of TB treatment options to cover drug resistant infections. Quinoxaline derivatives show very interesting biological properties (antibacterial, antiviral, anticancer, antifungal, antihelmintic, insecticidal) and evaluation of their medicinal chemistry is still in progress. In this review we report the properties and the recent developments of quinoxaline 1,4-di-N-oxide derivatives as potential anti-tuberculosis agents. Specific agents are reviewed that have excellent antitubercular drug properties, are active on drug resistant strains and non-replicating mycobacteria. The properties of select analogs that have in vivo activity in the low dose aerosol infection model in mice will be reviewed

Change in nutrient and dietary intake in european children with cystic fibrosis after a 6-month intervention with a self-management mhealth tool

Cystic Fibrosis (CF) is a life-long genetic disease, causing increased energy needs and a healthy diet with a specific nutrient distribution. Nutritional status is an indicator of disease prognosis and survival. This study aimed at assessing the effectiveness of a self-management mobile app in supporting patients with CF to achieve the dietary goals set by the CF nutrition guidelines. A clinical trial was conducted in pancreatic insufficient children with CF, followed in six European CF centres, where the self-management app developed within the MyCyFAPP project was used for six months. To assess secondary outcomes, three-day food records were compiled in the app at baseline and after 3 and 6 months of use. Eighty-four subjects (mean 7.8 years old) were enrolled. Compared to baseline, macronutrient distribution better approximated the guidelines, with protein and lipid increasing by 1.0 and 2.1% of the total energy intake, respectively, by the end of the study. Consequently, carbohydrate intake of the total energy intake decreased significantly (−2.9%), along with simple carbohydrate intake (−2.4%). Regarding food groups, a decrease in ultra-processed foods was documented, with a concomitant increase in meat and dairy. The use of a self-management mobile app to self-monitor dietary intake could become a useful tool to achieve adherence to guideline recommendations, if validated during a longer period of time or against a control group.</p